The present invention relates generally to medical adhesives and to methods of tissue closure, and, especially, to medical adhesives and to methods of tissue adhesion in which a mixture of isocyanate functional molecules or prepolymers is applied to tissue.
Each year approximately eleven million traumatic wounds are treated by emergency physicians in the United States. Traumatic wounds rival respiratory tract infections as the most common reason people seek medical care. Conventional methods of tissue closure (for example, sutures and staples) have several substantial limitations, including inability to produce fluid-tight closure, unsuitability for microsurgical applications, necessity for a second operation for removal, increased probability of inflammation and infection, and significant scarring and tissue injury during insertion. Medical tapes have been used for some applications, but medical tapes are limited by weak strength and problems with adherence to tissue. Treatment of lacerations with sutures often involves the injection of local anesthetic and use of needles, which can distress an already frightened patient. See, for example, McCaig L F, “National Hospital Ambulatory Medical Care Survey: 1992 Emergency Department Summary, Vital Health Stat., 1994, 245, 1-12; and Eland J M, Anderson J E, “The Experience of Pain in Children,” In: Jacox A K, ed. Pain, Boston, Mass.: Little Brown & Co., 1997 453-473. Suture wound repair is also painful and time-consuming. For quite some time, physicians have sought wound repair methods that require little time, do not require additional surgery, minimize the discomfort their patients, and produce a good cosmetic outcome.
In an attempt to achieve such goals, both biological and synthetic tissue adhesives have been developed. Applications of adhesives to biological tissue range from soft (connective) tissue adhesion to hard (calcified) tissue adhesion. Soft tissue adhesives are, for example, used both externally and internally for wound closure and sealing. Hard tissue adhesives are used, for example, to bond prosthetic materials to teeth and bone. Four main mechanisms of adhesion have been proposed for such tissue adhesives, including, mechanical interlocking, adsorption, diffusion theory, and electronic theory. Mechanical interlocking involves the penetration of the bonding agent into surface irregularities or porosity in the substrate surface as means for adhesion. Adsorption theory relies on the fact that if intimate interfacial molecular contact is achieved, interatomic and intermolecular forces will establish a strong joint. Diffusion theory states that the adhesion of polymers to substrates and each other requires mutual diffusion of polymer molecules or segments across the interface. Lastly, electronic theory suggests that electronic transfer between adhesive and adherent may lead to electrostatic forces that result in high intrinsic adhesion.
Unfortunately, currently available tissue adhesives have significant limitations. For example, biological tissue adhesives such as fibrin glues are effective in some uses, but are extremely expensive because they are derived from autologous tissue. Fibrin glue also suffers from relatively weak tensile strengths and labor-intensive means of production. Moreover, fibrinogen and thrombin obtained from human blood pose the risk of viral infection with, for example, acquired immune deficiency syndrome and/or hepatitis. See, for example, Spotniz W D, “History of Tissue Adhesives,” in Sierra D, Saits R, editors, Surgical Adhesives and Sealants, Current Technology and Applications, USA: Technomic, 1996; and Borst A H, et al., “Fibrin Adhesive: An Important Hemostatic Adjunct in Cardiovascular Operations,” J. Thorac. Cardiovasc. Surg., 1982, 84, 548-553.
Synthetic and semi-synthetic surgical adhesives, such as cyanoacrylate, urethane prepolymers, and gelatin-resorcinol-formaldehyde, have also been proposed. See, for example, Tseng Y-C, et al., “In Vivo Evaluation of 2-cyanoacrylates as Surgical Adhesives,” J. Appl. Biomater, 1990, 1, 11-22; Kobayashi H., et al., “Water-curable and Biodegradable Prepolymer, J. Biomed. Mater. Res., 1991, 25, 1481-1494; Matsuda T, et al., “A Novel Elastic Surgical Adhesive, Design Properties and In Vivo Performance,” Trans. Am. Soc. Artif Intern. Organ, 1986, 32, 151-156; and Matsuda T, et al., Department of a Compliant Surgical Adhesive Derived from Novel Flurinated Hexamethyiene Diisocyanate,” Trans. Am. Soc. Artif. Intern. Organ., 1989, 35, 381-383. However, these synthetic glues have several disadvantages including cytotoxicity, low degradation rates, and chronic inflammation induced by the sustained release of their degradation products (such as formaldehyde from cyanoacrylate polymers and gelatin-resorcinol-formaldehyde, and aromatic diamine from polyurethane). See, for example, Braumwald N S, et al., “Evaluation of Crosslinked Gelatin as a Tissue Adhesive and Hemostatic Agent: An Experimental Study,” Surgery, 1966, 59, 1024-1030; and Toriumi D, “Surgical Tissue Adhesive: Host Tissue Response, Adhesive Strength and Clinical Performance,” in Sierra D and Saits, R, ed. Surgical Adhesives and Sealants Current Technology and Applications, USA: Technomic, 1996: 61-69. Typically, synthetic glues are not suitable for internal use.
Cyanoacrylate macromonomers polymerize upon contact with water via chemistry similar to that used in well known “superglues”. In addition to the problems set forth above, however, the use of the cyano-acrylate group in cyanoacrylate polymers limits the versatility of the formulation, and other functional groups in the material must be compatible with the hypersensitive cyanoacrylate. Use of acrylate-functional polyethylene glycols allows for sealing and degradation (upon incorporation of lactic acid or glycolic acid repeat units in the polyethylene glycol precursor). However, curing requires the use of UV or other radiation. Given the penetration depth limitations of the light, radiation cure limits the use of this technology to thin films that are readily accessible to the light source.
It is thus desirable to develop improved, adhesives and methods of tissue adhesion for use in connection with living tissue.